PROJECT SUMMARY/ABSTRACT Cerebral palsy (CP) is a major neurodevelopmental disorder (prevalence 3:1000) that alters the course of normal brain development and impairs motor function. Although both prematurity and lack of oxygen to the developing brain are well-known causes of CP, current estimates suggest that up to one third of cases of CP may be genetic in origin. This represents a major shift for the field, which has almost exclusively focused on environmental contributions to date. Only a handful of genetic causes of CP are known, suggesting research in this area may be ?scratching the surface? of a vast genomic landscape, comparable to that seen in other neurodevelopmental disorders such as autism, intellectual disability and epilepsy. Although other inheritance patterns likely lead to CP in some patients, the central hypothesis of this proposal is that for many individuals with CP, mutations in a single gene may account for their condition. This project unites clinicians, researchers and advocacy stakeholders in order to discover and validate novel genetic causes of CP. The research team will employ whole exome sequencing to comb through the protein- coding regions of the genome to find causative mutations in previously unrecognized genes relevant to CP. We focus on individuals with cryptogenic CP (i.e. CP of unknown cause) and thus our cohort is highly enriched for strong genetic effect sizes. Our preliminary data indicate that deleterious mutations substantially contribute to cerebral palsy, and identify multiple high-confidence ?cerebral palsy genes.? These results suggest that although genes implicated in cases of cryptogenic CP are diverse, many map to common pathways. The goal of this application is to extend our preliminary findings to encompass a much larger cohort, providing the power required to define fundamental aspects of the genetic basis of CP. Whole exome sequencing of 500 parent-child trios is proposed to accomplish the following aims: 1) discover new genes and pathways that lead to CP when mutations occur; 2) pinpoint genes crucial for normal motor neurodevelopment; 3) distinguish bona fide mutations from benign DNA variants through a series of validation experiments in multiple model systems. Impact: Successful completion of the proposed aims will allow identification of new ?CP genes? with immediate diagnostic implications. These findings will also allow the construction of a genomic ?roadmap? of shared pathways connecting genetic forms of CP. In so doing, these studies will provide a window into CP neurobiology that will compare and contrast pathways between genetic and environmental forms of CP. Finally, this work will generate important primary data that will be shared within the recently established International Cerebral Palsy Genomics Consortium, spearheading international collaboration in CP genomics.